Personalized cancer therapy is one step closer

By Paul Basilio, MDLinx
Published August 2, 2017

Key Takeaways

New research from the lab of Yimon Aye, PhD, from Cornell University shows advances in the quest to provide personalized medicine via gene sequencing for patients with cancer. The research was recently published as two papers in Cell Chemical Biology.

Dr. Aye and her team have uncovered interesting facets of several well-known cancer-cell mutations that could inform treatment options and potentially produce more favorable outcomes. The lab used its novel chemical procedure, called “T-REX,” along with a patent-pending targeting molecule that was also developed in the Aye lab.

“People wonder why certain drugs are more efficient in one individual over another,” said Dr. Aye, a Milstein Sesquicentennial Fellow in the College of Arts and Sciences who also has a joint appointment in the Department of Biochemistry at Weill Cornell Medicine. “Our discovery gives us a foundation to think about and design inhibitors that will…be much more effective in the patients carrying certain mutations.”

The first paper explained how reduction-oxidation (redox) signaling affected the activity of specific enzymes, and how certain enzymes’ redox-specific processes could be harnessed for targeted drug design. This type of signaling is commonplace inside cells.

Research for the second paper was designed to test that theory. The group used its T-REX procedure coupled with a widely used strategy to deplete the cell of a specific protein of interest to determine which signals are affecting the response of a particular protein.

One obstacle faced by the team was that multiple variations, or isoforms, of the same protein can all catalyze the same cellular function. However, Dr. Aye noted that the nuances of biology rest in how individual isoforms are regulated.

“Some may be important in only certain types of tumors, or certain types of cells, so being able to discriminate one isoform over the other is important,” she added.

The group’s first key finding was that the interaction—or “cross-talk”—between cell signaling pathways is regulated depending on the concentration of the transcription factor called Nrf2. This fact is not clear unless Nrf2 signaling is able to be selectively stimulated, which is a method that Dr. Aye pioneered.

The second key finding involved a key mutation of cancer cells on the N-terminus–the start of a protein chain, which often contains key signaling information–that would make the cells more susceptible to certain targeted therapeutics than those without the mutation.

“What we’ve discovered as a strategy is a means to target this pathway in the cancer cells that carry selective mutations on this domain [the N terminus],” Dr. Aye said. “Potentially, patients can be genotyped to see if they carry these mutations, and they should respond much better to small molecules that activate antioxidant response.”

Dr. Aye noted that understanding the many complexities of oncogenesis and cell signaling is crucial to developing better therapies for cancer and other diseases.

“We could design much more selective therapeutics by understanding the underlying cross-talk,” she said.

To read more about these studies, click here

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